Collecting Duct Renin Synthesis and Secretion are Stimulated by Angiotensin (Ang) II via Protein Kinase C (PKC) Activation and cAMP Accumulation

Abstract

In rats and mice, Ang II type 1 receptor (AT1R) activation stimulates renin synthesis via PKC activation in the rat inner medulla CD (IMCD) cells. Because cAMP is an important second messenger for the Ang II signal transduction, we hypothesized that Ang II stimulates CD renin synthesis and release via PKC activation and cAMP accumulation. In mouse cortical CD cell line (M‐1 cells) treated with Ang II (8 hrs) we found increased renin mRNA in a dose‐dependent manner. PKC inhibition with Calphostin prevented this response. Likewise, Ang II increased renin and prorenin protein levels at 15 min with a sustained response for 2 hrs. Renin content measured in the cell culture media augmented in Ang II‐treated cells by 6 hrs (Ang II: 31±4 vs. 19±4 ng Ang I/hr/ml; p<0.05). Importantly, Ang II (10−7M) increased cAMP levels by 1 min (148±32 pmol/mg protein) reaching a peak at 30 min (290±27 vs. 44±0 pmol/mg protein; p<0.05). This response was prevented by PKA inhibition with H89 or PKI. Forskolin, an adenlyate cyclase activator, increased renin transcript in a dose‐dependent manner. Taken together, Ang II stimulates renin synthesis and secretion via PKC activation and cAMP stimulation in M‐1 cells; suggesting that during Ang II‐dependent hypertension, increased apical secretion of renin by the CD cells into the luminal fluid may augment intratubular Ang II formation, thus contributing to enhance distal nephron sodium reabsorption.